Ревматоїдний артрит (РА)

1. 1. Dedmon LE: The genetics of rheumatoid arthritis. Rheumatology (Oxford) 59(10):2661-2670, 2020. doi:10.1093/rheumatology/keaa232

2. 2. Block KE, Zheng Z, Dent AL, et al: Gut microbiota regulates K/BxN autoimmune arthritis through follicular helper T but not Th17 cells. J Immunol 196(4):1550-7, 2016. doi: 10.4049/jimmunol.1501904

3. 3. Wegner N, Wait R, Sroka A, et al: Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum 62(9):2662-72, 2010. doi: 10.1002/art.27552

1. 1. Gravallese EM, Firestein GS: Rheumatoid Arthritis - Common Origins, Divergent Mechanisms. N Engl J Med 388(6):529-542, 2023. doi:10.1056/NEJMra2103726

2. 2. Rantapaa-Dahlqvist S, de Jong BA, Berglin E, et al: Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 48:2741–2749, 2003. doi: 10.1002/art.11223

3. 3. Brink M, Verheul MK, Rönnelid J, et al: Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage. Arthritis Res Ther 17:25, 2015. doi: 10.1186/s13075-015-0536-2

4. 4. Sokolove J, Bromberg R, Deane KD, et al: Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS ONE 7(5):e35296, 2012. doi: 10.1371/journal.pone.0035296

5. 5. Kimbrough BA, Crowson CS, Davis JM 3rd, et al: Decline in Incidence of Extra-Articular Manifestations of Rheumatoid Arthritis: A Population-Based Cohort Study. Arthritis Care Res (Hoboken). Published online September 10, 2023. doi:10.1002/acr.25231

Subcutaneous rheumatoid nodules are not usually an early sign but eventually develop in up to 30% of patients, usually at sites of pressure and chronic irritation (eg, the extensor surface of the forearm, metacarpophalangeal joints, soles of feet) (1). Paradoxically, rheumatoid nodule formation can increase (accelerated nodulosis) in patients taking methotrexate, despite suppressing joint inflammation. Visceral nodules (eg, pulmonary) are usually asymptomatic and may occur in severe rheumatoid arthritis. Pulmonary nodules of rheumatoid arthritis cannot be distinguished from pulmonary nodules of other etiology without biopsy.

Other extra-articular complications include vasculitis causing leg ulcers, digital ischemia, or multiple mononeuropathy (mononeuritis multiplex); pleural or pericardial effusions;obliterative bronchiolitis; interstitial lung disease; pericarditis; myocarditis; lymphadenopathy; Felty syndrome; Sjögren syndrome; scleromalacia; and episcleritis.

Involvement of the cervical spine, generally in patients with longstanding destructive disease, can cause atlantoaxial subluxation and spinal cord compression; subluxation may worsen with extension of the neck (eg, during endotracheal intubation). Importantly, cervical spine instability is usually asymptomatic.

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Image courtesy of Kinanah Yaseen, MD.

Patients with rheumatoid arthritis are at increased risk for early coronary artery disease, metabolic bone disease such as osteopenia and osteoporosis, and various cancers (lung, lymphoproliferative disorders, and nonmelanoma skin cancers), which may be related to underlying, uncontrolled systemic inflammatory processes (2).

Приклади ревматоїдних вузликів

Ревматоїдні вузлики (ліктьова кістка)

Subcutaneous rheumatoid nodules (arrow) commonly form over pressure points as in this patient with olecranon bursitis. The nodules may be within subcutaneous tissue overlying the bursae or may be subperiosteal to the extensor surface of the ulna.

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By permission of the publisher. From Matteson E, Mason T: Atlas of Rheumatology. Edited by G Hunder. Philadelphia, Current Medicine, 2005.

Rheumatoid Nodules (Foot)

This photo shows rheumatoid nodules on the sole of the foot in a patient with rheumatoid arthritis. Rheumatoid nodules are often associated with surrounding fluid in a pressure-exacerbated "pseudobursa."

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DR P. MARAZZI/SCIENCE PHOTO LIBRARY

Rheumatoid Nodule (Hand)

This photo shows a rheumatoid nodule over the metacarpal joint of a patient with rheumatoid arthritis.

DR P. MARAZZI/SCIENCE PHOTO LIBRARY

Ревматоїдні вузлики (ліктьова кістка)

Subcutaneous rheumatoid nodules (arrow) commonly form over pressure points as in this patient with olecranon bursitis. The nodules may be within subcutaneous tissue overlying the bursae or may be subperiosteal to the extensor surface of the ulna.

... прочитати більше

By permission of the publisher. From Matteson E, Mason T: Atlas of Rheumatology. Edited by G Hunder. Philadelphia, Current Medicine, 2005.

Rheumatoid Nodules (Foot)

This photo shows rheumatoid nodules on the sole of the foot in a patient with rheumatoid arthritis. Rheumatoid nodules are often associated with surrounding fluid in a pressure-exacerbated "pseudobursa."

... прочитати більше

DR P. MARAZZI/SCIENCE PHOTO LIBRARY

Rheumatoid Nodule (Hand)

This photo shows a rheumatoid nodule over the metacarpal joint of a patient with rheumatoid arthritis.

DR P. MARAZZI/SCIENCE PHOTO LIBRARY

1. 1. Kimbrough BA, Crowson CS, Davis JM 3rd, et al: Decline in Incidence of Extra-Articular Manifestations of Rheumatoid Arthritis: A Population-Based Cohort Study. Arthritis Care Res (Hoboken). Published online September 10, 2023. doi:10.1002/acr.25231

2. 2. Figus FA, Piga M, Azzolin I, McConnell R, Iagnocco A: Rheumatoid arthritis: extra-articular manifestations and comorbidities. Autoimmun Rev 20(4):102776, 2021. doi:10.1016/j.autrev.2021.102776

Many disorders can simulate rheumatoid arthritis:

• Chronic crystal-induced arthritis (especially CPPD)

• Systemic lupus erythematosus (SLE)

• Sarcoidosis (rarely causes a polyarticular arthritis)

• Reactive arthritis

• Psoriatic arthritis

• Ankylosing spondylitis

• Infectious causes such as hepatitis C, parvovirus B19, alpha virus, Lyme disease, and Whipple disease

• Osteoarthritis

Some patients with crystal-induced arthritis, especially calcium pyrophosphate arthritis, may meet criteria for rheumatoid arthritis; however, synovial fluid examination should clarify the diagnosis. The presence of crystals makes rheumatoid arthritis unlikely, although calcium pyrophosphate crystal disease and rheumatoid arthritis may coexist in the same patient. Joint involvement and subcutaneous nodules can result from SLE, gout, cholesterol, and amyloidosis as well as rheumatoid arthritis; aspiration or biopsy of the nodules may occasionally be needed.

SLE usually can be distinguished if there are skin lesions on light-exposed areas, hair loss, oral and nasal mucosal lesions, absence of joint erosions in even long-standing arthritis, joint fluid that often has white blood cell counts < 2000/mcL (2 × 10⁹/L) (predominantly mononuclear cells), antibodies to double-stranded DNA, renal disease, and low serum complement levels. In contrast to rheumatoid arthritis, swan neck and ulnar deviation deformities in SLE (Jaccoud arthropathy) often lack marked synovial proliferation and are usually reducible.

Arthritis similar to rheumatoid arthritis can also occur in other rheumatic disorders (eg, polyarteritis, systemic sclerosis, dermatomyositis, or polymyositis), or there can be features of more than one disease, which suggests an overlap syndrome.

Sarcoidosis, Whipple disease, multicentric reticulohistiocytosis, and other systemic diseases may involve joints; other clinical features and tissue biopsy sometimes help differentiate these conditions. Acute rheumatic fever has a migratory pattern of joint involvement and evidence of antecedent streptococcal infection (culture or changing antistreptolysin O titer); in contrast, rheumatoid arthritis tends to involve joints in an additive and persistent manner over time.

Reactive arthritis can be differentiated by antecedent gastrointestinal or genitourinary symptoms; asymmetric involvement of predominantly large joints or with a diffusely swollen (sausage) digit (dactylitis) and pain at the Achilles insertion of the heel and sacroiliac joints; conjunctivitis; iritis; painless buccal ulcers; balanitis circinata; or keratoderma blennorrhagicum on the soles and elsewhere.

Psoriatic arthritis tends to be asymmetric and is not usually associated with RF, but clinical differentiation may be difficult in the absence of nail or skin lesions. Distal interphalangeal joint involvement and severely mutilating arthritis (arthritis mutilans) is strongly suggestive, as is the presence of dactylitis. Psoriatic arthritis may involve the sacroiliac joints and lower spine. Distinguishing between psoriatic arthritis and rheumatoid arthritis is important because response to some specific drugs differs.

Ankylosing spondylitis may be differentiated by spinal and axial joint involvement, absence of subcutaneous nodules, and a negative RF test. The HLA-B27 allele is present in 90% of White patients with ankylosing spondylitis.

Osteoarthritis can be differentiated by the joints involved; the absence of rheumatoid nodules, systemic manifestations, or high titer of RF or anti-CCP; and by synovial fluid white blood cell counts < 2000/mcL (2 × 10⁹/L). Osteoarthritis of the hands most typically involves the distal interphalangeal (DIP) joints, bases of the thumbs, and proximal interphalangeal (PIP) joints. Osteoarthritis may involve the metacarpophalangeal joints, but usually less so than the other joints, and typically spares the ulnar styloid area and wrist. Rheumatoid arthritis does not affect the DIP joints.

1. 1. Nishimura K, Sugiyama D, Kogata Y, et al: Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med 146(11):797-808, 2007. doi:10.7326/0003-4819-146-11-200706050-00008

2. 2. Ingegnoli F, Castelli R, Gualtierotti R: Rheumatoid factors: clinical applications. Dis Markers. 2013;35(6):727-734. doi:10.1155/2013/726598

3. 3. Wilson A, Yu HT, Goodnough LT, Nissenson AR. Prevalence and outcomes of anemia in rheumatoid arthritis: a systematic review of the literature. Am J Med. 2004;116 Suppl 7A:50S-57S. doi:10.1016/j.amjmed.2003.12.012

Lifestyle measures measure play an important role in disease management, and detailed recommendations have been provided by the ACR (3) and EULAR (4). These measures include regular exercise, maintaining a healthy diet, achieving and maintaining a healthy weight, moderate alcohol consumption, smoking cessation, and worksite modifications if needed for active work participation. Quality sleep should also be encouraged, because poor sleep may exacerbate pain.

A nutritious diet, such as the "Mediterranean diet" which is high in fruits and vegetables and low in processed food, is encouraged. In addition to the cardiovascular benefits of the Mediterranean diet, limited observational data suggest that it also has beneficial effects on pain in patients with rheumatoid arthritis. Some patients have food-associated exacerbations (5); however, no specific foods have reproducibly been shown to exacerbate or lessen the symptoms of rheumatoid arthritis. Substituting omega-3 fatty acids (in fish oils) for dietary omega-6 fatty acids (in meats) partially relieves symptoms in some patients, which are thought to act by transiently decreasing production of inflammatory prostaglandins and possibly by modifying the gut microbiome.

Food and diet misinformation targeting rheumatoid arthritis patients is common, and patients should be directed to reliable sources of information.

Joint splinting may relieve severe symptoms of pain or compressive neuropathies. Cold may be applied to reduce joint pain and swelling. Orthopedic or athletic shoes with good heel and arch support are frequently helpful; metatarsal supports placed posteriorly (proximal) to painful metatarsophalangeal joints decrease the pain of weight bearing. Molded shoes may be needed for severe deformities. Occupational therapy and self-help devices enable many patients with debilitating rheumatoid arthritis to perform activities of daily living.

Exercise should proceed as tolerated. During acute inflammation, passive range-of-motion exercise helps prevent flexion contractures. Heat therapy can be applied to help alleviate stiffness. Range-of-motion exercises done in warm water are helpful because heat improves muscle function by reducing stiffness and muscle spasm. However, contractures can be prevented and muscle strength can be restored more successfully after inflammation begins to subside; active exercise (including walking and specific exercises for involved joints) to restore muscle mass and preserve range of joint motion are recommended. Flexion contractures may require intensive exercise, casting, or immobilization (eg, splinting) in progressively more stretched-open positions. Paraffin baths can warm digits and facilitate finger exercise.

Massage by trained therapists, traction, and deep heat treatment with diathermy or ultrasonography may be transiently useful adjuncts to pharmacologic therapy.

Surgery may be considered if pharmacologic therapy is unsuccessful. Surgery must always be considered in terms of the total disease burden and patient expectations. For example, deformed hands and arms limit crutch use during rehabilitation; seriously affected knees and feet limit benefit from hip surgery. Reasonable objectives for each patient must be determined, and function must be considered; straightening ulnar-deviated fingers may not improve hand function. Surgery is preferably performed during periods of disease quiescence or low disease activity, but may need to be done during active disease.

Arthroplasty with prosthetic joint replacement is indicated if damage severely limits function; total hip and knee replacement outcomes are generally favorable (6, 7). Prosthetic hips and knees may limit vigorous activity (eg, competitive athletics). Excision of subluxed painful metatarsophalangeal joints may greatly aid walking. Thumb fusions may provide stability for pinch function. Neck fusion may be needed for significant C1-2 subluxation with severe pain or potential for spinal cord compression. Arthroscopic or open synovectomy can relieve joint inflammation but only temporarily unless disease activity can be controlled. Withholding some immunosuppressive medications (not necessarily methotrexate) at the time of arthroplasty should be considered to limit the risk of infection (8). Even low-dose prednisone (< 7.5 mg a day) may increase infectious risk.

1. 1. Fraenkel L, Bathon JM, England BR, et al: 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 73(7):1108-1123, 2021. doi:10.1002/art.41752

2. 2. Smolen JS, Landewé RBM, Bijlsma JWJ, et al: EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 79(6):685-699, 2020. doi:10.1136/annrheumdis-2019-216655

3. 3. England BR, Smith BJ, Baker NA, et al: 2022 American College of Rheumatology Guideline for Exercise, Rehabilitation, Diet, and Additional Integrative Interventions for Rheumatoid Arthritis. Arthritis Rheumatol 75(8):1299-1311, 2023. doi:10.1002/art.42507

4. 4. Gwinnutt JM, Wieczorek M, Balanescu A, et al: 2021 EULAR recommendations regarding lifestyle behaviours and work participation to prevent progression of rheumatic and musculoskeletal diseases. Ann Rheum Dis 82(1):48-56, 2023. doi:10.1136/annrheumdis-2021-222020

5. 5. Tedeschi SK, Frits M, Cui J, et al: Diet and Rheumatoid Arthritis Symptoms: Survey Results From a Rheumatoid Arthritis Registry. Arthritis Care Res (Hoboken). 2017;69(12):1920-1925. doi:10.1002/acr.23225

6. 6. Zhang Y, Chu SS, Liu K, Huang Q, Wang Y: Outcomes in patients with rheumatoid versus osteoarthritis for total hip arthroplasty: a meta-analysis and systematic review. Semin Arthritis Rheum 56:152061, 2022. doi:10.1016/j.semarthrit.2022.152061

7. 7. Burn E, Edwards CJ, Murray DW, et al: The effect of rheumatoid arthritis on patient-reported outcomes following knee and hip replacement: evidence from routinely collected data. Rheumatology (Oxford) 58(6):1016-1024, 2019. doi:10.1093/rheumatology/key409

8. 8. Goodman SM, Springer B, Guyatt G, et al: 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty. Arthritis Rheumatol 69(8):1538-1551, 2017. doi:10.1002/art.40149

(See table Medications Used to Treat Rheumatoid Arthritis for adverse effects of other medications used to treat rheumatoid arthritis.)

Conventional synthetic (nonbiologic) DMARDs slow the progression of rheumatoid arthritis and are indicated for nearly all patients with rheumatoid arthritis. They differ from each other chemically and pharmacologically. Many take weeks or months to have an effect. Many conventional synthetic DMARDs result in evidence of decreased damage on imaging studies, presumably reflecting decreased disease activity (4). Patients should be fully apprised of the risks of these medications and monitored closely for evidence of toxicity.

When using conventional synthetic DMARDs, the following principles should be considered:

• Combinations of DMARDs may be more effective than a single agent. For example, hydroxychloroquine, sulfasalazine, and methotrexate together are more effective than methotrexate alone or the other two together (5).

• Combining a DMARD with a biologic DMARD, such as methotrexate plus a tumor necrosis factor (TNF) inhibitor or a rapidly tapered corticosteroid, may be more effective than using a single DMARD alone.

Methotrexate is a folate antagonist with immunosuppressive effects at high dose. It is anti-inflammatory at the lower doses used in rheumatoid arthritis. Clinical benefit is usually observed within 6 weeks, but it may take up to 3 months or more. Methotrexate should be used with caution, if at all, in patients with hepatic dysfunction or renal impairment. Frequent alcohol consumption should be avoided. Supplemental folate, typically given as folic acid 1 mg orally once/day, reduces the likelihood of adverse effects. Complete blood count (CBC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and albumin and creatinine level should be determined about every 8 to 12 weeks. When used early in the course of rheumatoid arthritis, efficacy may be comparable to the biologic agents. Severe relapses of arthritis can occur after withdrawal of methotrexate. Paradoxically, rheumatoid nodules may enlarge with methotrexate therapy. In rheumatoid arthritis patients with stable parenchymal lung disease, methotrexate can be continued with close monitoring of their respiratory status, if the methotrexate is controlling joint inflammation.

Hydroxychloroquine can also control symptoms of mild rheumatoid arthritis. Funduscopic examination should be done and visual fields should be assessed before and every 12 months during treatment. Hydroxychloroquine should be stopped if no joint improvement occurs after 9 months.

Sulfasalazine can alleviate symptoms and slow development of joint damage. It is usually given as enteric-coated tablets. Benefit should occur within 3 months. Enteric coating or dose reduction may increase tolerability. Because neutropenia may occur early, CBCs should be obtained after 1 to 2 weeks and then about every 12 weeks during therapy. AST and ALT should be obtained at about 6-month intervals and whenever the dose is increased. In male patients, sulfasalazine may cause reversible oligospermia.

Leflunomide interferes with an enzyme involved with pyrimidine metabolism. It is about as effective as methotrexate but is less likely to suppress bone marrow, cause abnormal liver function, or cause pneumonitis. Alopecia and diarrhea are fairly common at the onset of therapy but may resolve with continuation of therapy.

Tumor necrosis factor inhibitors (eg, adalimumab, etanercept, golimumab, certolizumab pegol, infliximab, and their biosimilars) reduce the progression of erosions and reduce the number of new erosions. Although not all patients respond, many have a prompt, dramatic feeling of well being, sometimes with the first injection. Inflammation is often dramatically reduced. These agents are often added to methotrexate therapy to increase the effect and possibly prevent the development of drug-neutralizing antibodies.

Safety data suggest treatment with TNF inhibitors may be continued during the first and second trimesters of pregnancy, with most professional societies recommending they be stopped in the third trimester. However, due to its pegylated formulation, certolizumab is a TNF inhibitor that does not cross the placenta and can be continued throughout the pregnancy (6). TNF inhibitors should usually be stopped before major surgery to decrease the risk of perioperative infection (7). TNF inhibitors may predispose to heart failure and thus are relatively contraindicated in stage 3 and stage 4 heart failure. There is a minimal risk of lymphoma in rheumatoid arthritis patients who are being treated with TNF inhibitors. 2015 ACR guidelines conditionally recommended using DMARDs, rituximab, or abatacept instead of TNF inhibitors in patients with history of lymphoma (8). Evidence regarding solid tumors in TNF inhibitors is mixed. Other possible adverse events of TNF inhibitors include injection site reaction, acute and delayed infusion reaction, demyelinating disease, granulomatous diseases such as sarcoidosis, cytopenias (especially neutropenia), cutaneous vasculitis, psoriasis, and rarely antineutrophilic cytoplasmic associated vasculitis. A major concern is the reactivation of mycobacterial or fungal infections.

Biosimilar forms of several TNF inhibitors (and other biologic agents) are commercially available, and additional agents are in development. Biosimilars are highly similar to the reference product in terms of efficacy and toxicity, but they may differ slightly in their molecular structure. (See also U.S. Food and Drug Administration: Biosimilar Product Information and European Medicines Agency: Biosimilars.)

Tocilizumab is an interleukin (IL-6) inhibitor and has clinical efficacy in patients who have responded incompletely to other biologic agents. It may be used as monotherapy but can also be given in combination with methotrexate or another conventional synthetic DMARD.

Sarilumab is an IL-6 inhibitor. It is available for adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to or are intolerant of one or more DMARDs.

Abatacept, a soluble fusion cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) immunoglobulin, is indicated for patients with rheumatoid arthritis with an inadequate response to other DMARDs. Abatacept is conditionally recommended over other biologic DMARDs in patients with rheumatoid arthritis and non-tuberculous mycobacterial lung disease.

Rituximab is an anti-CD 20 antibody that depletes B cells. It can be used in patients refractory to other treatments. Response is often delayed but may last 6 months. The course can be repeated after 6 months. Mild infusion reactions are common, and analgesia, corticosteroids, diphenhydramine, or a combination may need to be given concomitantly. Rituximab therapy has rarely been associated with progressive multifocal leukoencephalopathy (as have other immunosuppressive agents), mucocutaneous reactions, delayed leukopenia, and hepatitis B reactivation with hepatic necrosis. Patients taking rituximab may have a blunted immune response to the COVID-19 vaccine and have poorer outcomes if infected with SARS-CoV-2. Therefore, rituximab is now generally reserved for patients who did not respond to other biologic DMARDs (including a combined TNF inhibitor and methotrexate) and to those with lymphoproliferative disorders.

Rituximab therapy might be gradually discontinued if the patient has had low disease activity or been in remission for at least 6 months.

Anakinra is a recombinant interleukin-1 (IL-1) receptor antagonist. IL-1 is heavily involved in the pathogenesis of rheumatoid arthritis. Adverse effects include infection and leukopenia. It is rarely used because it lacks efficacy compared with other biologics and because it is a daily injection.

Although there are some differences among agents, the most serious concern with biologic and targeted synthetic DMARDs is infection, particularly with reactivated tuberculosis. Patients should be screened for tuberculosis with purified protein derivative (PPD) or an interferon-gamma release assay. Pretreatment serologic testing for hepatitis B and C should also be performed prior to treatment with DMARDs. Other serious infections can occur, including sepsis, invasive fungal infections, and infections due to other opportunistic organisms. Patients should be up to date on vaccinations prior to treatment with a biologic agent.

Janus kinase (JAK) inhibitors are targeted synthetic agents, also referred to as small molecule agents, that interfere with the communication between cells that coordinate inflammation by inhibiting the enzyme JAK. JAK inhibitors are administered orally and include the following (see also table Medications Used to Treat Rheumatoid Arthritis):

• Tofacitinib, given with or without concomitant methotrexate to patients who do not respond to methotrexate alone or to other biologic agents.

• Upadacitinib, given to adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.

• Baricitinib, indicated for adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF inhibitors.

JAK inhibitors carry an increased incidence of herpes zoster; thus vaccination against zoster is strongly suggested prior to use of these medications. Patients should also be assessed for cardiovascular risk factors given the potential increased risk of major adverse cardiovascular events (MACEs; eg, myocardial infarction, stroke, venous thromboembolism, pulmonary embolism) with JAK inhibitors. A prospective, randomized, open-label study comparing tofacitinib (5 and 10 mg doses) with TNF inhibitors found that, after a median follow-up of 4 years, there was a higher risk of MACEs and cancer with tofacitinib than with TNF inhibitors, especially in patients over age 50 years and with at least 1 risk factor for cardiovascular disease (9). Although the study was limited to tofacitinib, these safety concerns have been applied to all of the JAK inhibitors until more data are available.

Other immunosuppressive agents, including azathioprine or cyclosporine (an immunomodulatory medication), have less efficacy and are rarely used because of an increased risk of toxicity. Thus, they are used only for patients in whom treatment with more traditional DMARDs has failed.

Aspirin is no longer used for rheumatoid arthritis because effective doses are often toxic. Only one NSAID should be given at a time (see table NSAID Treatment of Rheumatoid Arthritis), although patients may also take aspirin at ≤ 325 mg/day for its antiplatelet cardioprotective effect. Because the maximal response for NSAIDs can take up to 2 weeks, doses should be increased no more frequently than this. Doses of drugs with flexible dosing can be increased until response is maximal or maximum dosage is reached. All NSAIDs treat the symptoms of rheumatoid arthritis and decrease inflammation but do not alter the course of the disease; thus, they are only used adjunctively.

NSAIDs inhibit cyclooxygenase (COX) enzymes and thus decrease production of prostaglandins. Some prostaglandins under COX-1 control have important effects in many parts of the body (ie, they protect gastric mucosa and inhibit platelet adhesiveness). Other prostaglandins are induced by inflammation and are produced by COX-2. Selective COX-2 inhibitors, also called coxibs (eg, celecoxib), seem to have efficacy similar to nonselective NSAIDs and are slightly less likely to cause gastrointestinal toxicity; however, they are not less likely to cause renal toxicity. Celecoxib 200 mg orally once/day has a comparable cardiovascular safety profile to nonselective NSAIDs. It remains unclear whether full-dose celecoxib (200 mg orally 2 times a day ) has cardiovascular risks comparable to the nonselective NSAIDs.

NSAIDs should generally be avoided in patients with previous peptic ulcer disease or dyspepsia; gastric acid suppressive therapy (eg, proton pump inhibitors) should be given to these patients and others at increased risk for gastric ulceration (eg, older adults) if an NSAID is used. Other possible adverse effects of all NSAIDs include headache, confusion and other central nervous system symptoms, increased blood pressure, edema, and decreased platelet function; however, celecoxib has no significant antiplatelet effect. NSAIDs may increase cardiovascular risk (see Treatment of Pain/Nonopioid Analgesics). Creatinine levels can rise reversibly because of inhibited renal prostaglandins and reduced renal blood flow; rarely, interstitial nephritis can occur. Patients with urticaria, rhinitis, or asthma caused by aspirin can have the same problems with these other NSAIDs, but celecoxib may not cause these allergic problems.

NSAIDs should be used at the lowest possible dose needed to mitigate their adverse effects.

Systemic corticosteroids decrease inflammation and other symptoms more rapidly than other medications used for rheumatoid arthritis. However, they do not prevent joint destruction, and their clinical benefit often diminishes with time. Furthermore, rebound often follows the withdrawal of corticosteroids in active disease. Because of their long-term adverse effects, corticosteroids are usually given only for short periods of time to maintain function until a DMARD has taken effect.

Corticosteroids may be used for severe joint or systemic manifestations of rheumatoid arthritis (eg, vasculitis, pleurisy, pericarditis). Relative contraindications include peptic ulcer disease, hypertension, untreated infections, diabetes mellitus, and glaucoma. The risk of latent tuberculosis should be considered before corticosteroid therapy is begun.

Intra-articular injections of depot corticosteroids may temporarily help control pain and swelling in particularly painful joints. Triamcinolone hexacetonide may suppress inflammation for the longest time. Triamcinolone acetonide and methylprednisolone acetate are also effective. No single joint should be injected with a corticosteroid more than 3 to 4 times a year, as too-frequent injections may accelerate joint destruction. Because injectable corticosteroid esters are crystalline, local inflammation transiently increases within a few hours in < 2% of patients receiving injections. Although infection is rare, with one study reporting a rate of approximately 1 of 2,000 procedures (10), infection must be considered if pain occurs > 24 hours after injection.

1. 1. Fraenkel L, Bathon JM, England BR, et al: 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 73(7):1108-1123, 2021. doi:10.1002/art.41752

2. 2. Smolen JS, Landewé RBM, Bijlsma JWJ, et al: EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 79(6):685-699, 2020. doi:10.1136/annrheumdis-2019-216655

3. 3. Huscher D, Thiele K, Gromnica-Ihle E, et al: Dose-related patterns of glucocorticoid-induced side effects. Ann Rheum Dis 68(7):1119-1124, 2009. doi:10.1136/ard.2008.092163

4. 4. Moreland LW, O'Dell JR, Paulus HE, et al: A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2012;64(9):2824-2835. doi:10.1002/art.34498

5. 5. O'Dell JR, Haire CE, Erikson N, et al: Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 334(20):1287-1291, 1996. doi:10.1056/NEJM199605163342002

6. 6. Sammaritano LR, Bermas BL, Chakravarty EE, et al: 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Care Res (Hoboken) 72(4):461-488, 2020. doi:10.1002/acr.24130

7. 7. Goodman SM, Springer BD, Chen AF, et al: 2022 American College of Rheumatology/American Association of Hip and Knee Surgeons guideline for the perioperative management of antirheumatic medication in patients with rheumatic diseases undergoing elective total hip or total knee arthroplasty. Arthritis Care Res (Hoboken) 74(9):1399-1408, 2022. doi:10.1002/acr.24893

8. 8. Singh JA, Saag KG, Bridges SL Jr, et al: 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 68(1):1-26, 2016. doi:10.1002/art.39480

9. 9. Ytterberg SR, Bhatt DL, Mikuls TR, et al: Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med 386(4):316-326, 2022. doi:10.1056/NEJMoa2109927

10. 10. Petersen SK, Hansen I, Andreasen RA: Low frequency of septic arthritis after arthrocentesis and intra-articular glucocorticoid injection. Scand J Rheumatol. 2019;48(5):393-397. doi:10.1080/03009742.2019.1584329

1. 1. Black RJ, Lester S, Tieu J, et al. Mortality estimates and excess mortality in rheumatoid arthritis. Rheumatology (Oxford). 2023;62(11):3576-3583. doi:10.1093/rheumatology/kead106

2. 2. Kerola AM, Kazemi A, Rollefstad S, et al: All-cause and cause-specific mortality in rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis: a nationwide registry study. Rheumatology (Oxford). 2022;61(12):4656-4666. doi:10.1093/rheumatology/keac210

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